Anatomical location reflects distinct cytogenetic signatures in intracranial meningiomas

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OBJECTIVE: Anatomical location correlates with mutational and histopathological subtypes in meningiomas. However, the relationship between anatomical distribution and arm-level chromosomal copy number alterations (CNAs), central mediators of meningioma biology, has not been systematically characterized. METHODS: A total of 740 primary sporadic intracranial meningiomas (538 WHO grade I, 194 WHO grade II, 8 WHO grade III) were analyzed for anatomical location: anterior midline skull base (n = 100), lateral (supratentorial) skull base (n = 120), infratentorial skull base (n = 101), midline convexity (n = 157), lateral convexity (n = 201), infratentorial non-skull base (n = 54), and other (n = 7). Histopathological grade was extracted from the medical record. Chromosome arm-level CNAs were derived from whole-genome microarrays. Angiomatous meningiomas (n = 55) were excluded from cytogenetic analyses. Overall CNA burden was defined as the total number of chromosome arm gains and losses. High-risk CNA burden was quantified based on alterations previously associated with poor progression-free survival (PFS). Hierarchical and nonnegative matrix factorization (NMF) clustering analyses were applied to CNA profiles to identify genomic subgroups. RESULTS: WHO grade and molecularly Integrated Grade (IG) differed markedly across anatomical location (both p = 0.0001). Anterior midline skull base and infratentorial skull base meningiomas were predominantly IG 1/low grade, whereas supratentorial convexity meningiomas were enriched for IG 2 and 3/high-grade tumors. Proliferative index and CNA burden mirrored these patterns, with minimal overall and high-risk CNAs in anterior midline and infratentorial skull base tumors and higher-burden CNA profiles in supratentorial convexity and intraventricular meningiomas. Across all analyses, lateral (supratentorial) skull base meningiomas occupied an intermediate status, falling between lower-risk infratentorial skull base tumors and more aggressive supratentorial convexity tumors. Hierarchical clustering and NMF independently validated these findings by identifying similar genomic profiles between lateral (supratentorial) skull base and supratentorial convexity meningiomas. PFS analyses demonstrated that gross-total resection confers local disease control compared to subtotal resection, especially in biologically benign anatomical locations. CONCLUSIONS: Meningiomas exhibit a significant association between their anatomical origin and chromosomal alterations. These findings suggest that developmental factors may shape divergent cytogenetic trajectories and that anatomical context may serve as a proxy for guiding assessment of meningioma behavior.

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